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We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Aims: Heterogeneity in the rate of β‐cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease‐modifying clinical trials. Integrative analyses of baseline multi‐omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. Methods: We collected samples in a pan‐European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi‐Omics Factor Analysis to identify molecular signatures correlating with post‐diagnosis decline in β‐cell mass measured as fasting C‐peptide. Results: Two molecular signatures were significantly correlated with fasting C‐peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non‐lymphoid cell interactions and G‐protein coupled receptor signalling events that were inversely associated with a rapid decline in β‐cell function. The second signature was related to translation and viral infection was inversely associated with change in β‐cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid β‐cell decline. Conclusions: Features that differ between individuals with slow and rapid decline in β‐cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to describe the rationale and design of Project FOREVER (Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability). Design: Project FOREVER will build a comprehensive database of clinical eye and vision data collected from ~280 000 adults at 100 optician stores across Denmark. The FOREVER database (FOREVERdb) includes detailed data from refraction, visual acuity, intraocular pressure, corneal thickness, visual field assessments and retinal fundus images. Linkage to the comprehensive Danish national registries with, that is diagnostic and prescribing data permits investigation of rare associations and risk factors. 30 000 individuals over 50 also provide a saliva sample for later genetic studies and blood pressure measurements. Of these 30 000, 10 000 will also get optical coherence tomography (OCT) nerve and retinal scans. This subpopulation data is reviewed by ophthalmologists for disease detection. All participants will be asked to complete a questionnaire assessing lifestyle, self‐perceived eye health and general health. Enrolment of participants began in April 2022. Perspective: The FOREVERdb is a powerful tool to answer a wide range of research questions that can pave the way for better eye health. This database will provide valuable insights for future studies investigating the correlations between eye and general health in a Danish population cohort, enabling research to identify potential risk factors for a range of diseases. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex‐specific factors.It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immune response and genetic diversity.We performed a case–control study and included 13,210 individuals with migraine and 86,738 controls. All participants were part of the Danish Blood Donor Study Genomic Cohort. Participants were genotyped and 111 HLA alleles on 15 HLA genes were imputed. We examined the association between HLA alleles and migraine subtypes, considering sex‐specific differences.We found no association between HLA alleles and migraine, neither overall, nor in the sex‐specific analysis. In the migraine subtype analysis, three HLA alleles were associated with migraine without aura; however, these associations could not be replicated in an independent Icelandic cohort (2191 individuals with migraine without aura and 278,858 controls). Furthermore, we found no association between HLA alleles and migraine with aura or chronic migraine.We found no evidence of an association between the HLA system and migraine, suggesting that genetic factors related to the HLA system do not play a significant role in migraine susceptibility. [ABSTRACT FROM AUTHOR]

Background: The CC chemokine receptor 5 (CCR5) is a suggested receptor for Staphylococcus aureus leukotoxin ED. Homozygosity for the Δ32 deletion (CCR5Δ32) protects against human immunodeficiency virus infection and possibly also against leukotoxin ED. We examined the impact of CCR5Δ32 on the susceptibility to S. aureus infection, all-cause infections, and S. aureus nasal carriage, respectively, and on the concentrations of circulating chemokines in blood donors., Methods: We included 95,406 participants from the Danish Blood Donor Study (DBDS) genotyped for >650,000 single nucleotide polymorphisms. The CCR5Δ32 (rs333, MAF: 0.12) was imputed from a reference panel and validated. Infectious outcomes were identified by diagnosis codes and redeemed prescription of antibiotics in national health registers. Data on S. aureus nasal carriage and forty-seven inflammatory biomarkers were available for 6721 and 7811 participants, respectively. Cox, logistic, and linear regression models adjusted for relevant confounders were used to explore said associations., Findings: During more than 700,000 person-years of observation, we found that CCR5Δ32 was associated with neither an increased risk of redeemed dicloxacillin, hospital-treated S. aureus-associated infection (replicated in 345,996 Icelanders), redeemed antibiotics, all-cause infection, and nor with S. aureus nasal carriage. We discovered an association between CCR5Δ32 and elevated CCL4 concentrations, which were 1.26-fold higher in Δ32-heterozygotes (95%-CI: 1.23-1.30) and 2.64-fold higher in Δ32-homozygotes (95%-CI: 2.41-2.90) compared with wildtype homozygotes. Conversely, concentrations of CCL2, CXCL-10, and CCL11 were slightly lower among Δ32-heterozygotes., Interpretation: Results from this CCR5Δ32 high-prevalent cohort do not support the idea that CCR5Δ32 affects the risk of S. aureus carriage or infection to any relevant degree, in this northern European context. CCL4 was the main chemokine affected by CCR5Δ32 and was observed in higher concentration among Δ32-carriers. This study cannot rule out that S. aureus is a previous driver of CCR5Δ32 selection., Funding: The Health Research Fund of Central Denmark Region, Aarhus University, Danish Administrative Regions, Bio- and Genome Bank Denmark, Danish Blood Donor Research Foundation, Aase & Ejnar Danielsens Foundation, Højmosegård Grant, National Institute of Allergy and Infectious Diseases, and A.P. Møller Foundation for the Advancement of Medical Science., Competing Interests: Declaration of interests CE has received an unrestricted grant from Abbott Diagnostics and Novo Nordisk, no personal fees. SB reports grants from Innovation Fund Denmark, from Novo Nordisk Foundation during the conduct of the study, and personal fees from Intomics A/S and Proscion A/S, outside the submitted work. All other authors declare no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions. Results can be accessed at https://h2.cpr.ku.dk/ ., (© 2024. The Author(s).)

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13-1.27], p = 3.92 × 10 -9 ). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p < 0.05, two-sided). Participants for the replication were included from 2015 to 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders., (© 2024. The Author(s).)

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets., (© 2024. The Author(s).)

Competing Interests: Kirsten Grønbæk has received research funding and/or consultancy fees from Janssen Pharma and GSK. Carsten Utoft Niemann has received research funding and/or consultancy fees from Abbvie, AstraZeneca, Janssen, Octapharma, Beigene, Genmab, CSL Behring, Takeda, Lilly, and MSD. Anne‐Mette Lebech has received unrestricted research grant from Gilead and consultancy fees from GSK, MSD, and Pfizer.

Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood., Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis., Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023., Exposure: Genotype., Main Outcomes and Measures: Pericarditis., Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein β (encoded by CEBPB)., Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.

Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleotide polymorphism-based heritability of trust to be 6% (95% confidence interval = (2.1, 9.9)). In our discovery cohort (n = 25,819), we identified one significantly associated locus (lead variant: rs12776883) in an intronic enhancer region of PLPP4, a gene highly expressed in brain, kidneys, and testes. However, we could not replicate the signal in an independent set of donors who were phenotyped a year later (n = 8063). In the subsequent meta-analysis, we found a second significantly associated variant (rs71543507) in an intergenic enhancer region. Overall, our work confirms that social trust is heritable, and provides an initial look into the genetic factors that influence it., (© 2024. The Author(s).)